Antimicrobials: New drugs, new resistance

Ten years ago, infection control was the biggest trend in tackling hospital-based infectious diseases. Now the new hot area is antibiotic stewardship.

Ten years ago, infection control was the biggest trend in tackling hospital-based infectious diseases. Now the new hot area is antibiotic stewardship, said Keith Kaye, FACP, at a session on antimicrobial therapy at Internal Medicine 2011.

“Infection control is still important, but if you don't have a stewardship program at your hospital, there is a good chance you'll see one in the next five years,” said Dr. Kaye, professor of medicine at Wayne State University in Detroit and corporate medical director of infection prevention, hospital epidemiology and antimicrobial stewardship at Detroit Medical Center.

Keith Kaye FACP Photo by Kevin Berne
Keith Kaye, FACP. Photo by Kevin Berne.

Included in this change of focus is a shift in dosing strategy, from a long course of multidrug therapy to a shorter course of more aggressive therapy, he added.

“Rather than thinking more and longer is better, we're thinking about the collateral damage—more colonizing bacteria is the big risk—and looking at more potent drugs for shorter durations,” Dr. Kaye said.

Of course, picking the right treatment means knowing which bacteria and strains are currently resistant or responsive to a given drug, among other things. Dr. Kaye offered an overview of currently available drugs and how they fare against several common infectious diseases and bacteria seen in the hospital.


Resistance to carbapenems is the biggest threat in treating hospital-based infections currently, Dr. Kaye said. Patients at particular risk of carbapenem-resistant infection include those with prolonged exposure to health care settings (ICU or otherwise), repeated antibiotic exposures and indwelling devices.

“If you think about the typical patient you discharge or accept from a long-term acute care center, they fit many of these risk factors,” Dr. Kaye said.

Carbapenem resistance is particularly an emerging problem with Pseudomonas, Acinetobacter and Enterobacteriaceae. That's bad news, because there are few treatment options as it is for gram-negative bacterial infections, he said.

“Once we lose carbapenems, along with the other beta-lactams [antibiotics] and quinolones, we are often stuck using agents such as colistin, an old antimicrobial that was shelved and forgotten for toxicity reasons,” Dr. Kaye said.

A landmark publication in the April 15, 2008 Journal of Infectious Diseases identified the main pathogens that have increased in prevalence and degree of resistance in hospitals as Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia, Acinetobacter baumannii, Pseudomonas seruginosa and Enterobacter species—forming the acronym ESKAPE. A newer version also includes a “C”, for Clostridium difficile, Dr. Kaye said.

“The article pointed out that many of the new agents that have come out address issues on the gram-positive front, particularly for MRSA [methicillin-resistant Staphylococcus aureus] or VRE [vancomycin-resistant enterococci], but few if any have adequately addressed emergence among gram-negative organisms,” he said.

If resistance only gave physicians fewer options for treatment without impacting patient outcomes, it wouldn't be such a big deal, Dr. Kaye said. But several studies have found a mortality risk two to three times greater with MRSA compared to methicillin-susceptible Staphylococcus aureus, while another found about a threefold risk with multidrug-resistant (MDR) versus drug-susceptible Acinetobacter, he said.

“Typically you will also see a one-and-a-half to twofold increase in duration of hospitalizations and hospital costs [with resistant infections]—even after adjusting for severity of illness and differences in affected patient populations,” he said. “So whether you are talking about gram positives or negatives, resistance drives poor outcomes and increased hospital costs.”

Newer antimicrobials: The gram positives

Some of the so-called “newer” antimicrobials aren't that new in terms of how long they have been around, but clinicians and researchers are still trying to determine how best to use them, Dr. Kaye said.

An example is linezolid (brand name: Zyvox), the first and only approved oxazolidinone, which has very broad-spectrum gram-positive activity against many strains of MRSA, VRE, pneumococci and enterococci. It's indicated by the Food and Drug Administration for pneumonia, including ventilator-associated pneumonia, and skin and soft-tissue infections (SSTIs) caused by gram-positive cocci. It doesn't perform well against bloodstream infections, Dr. Kaye noted.

One of the major advantages of the drug, which comes in oral and intravenous forms, is that it is highly bioavailable—”pretty much 100%,” Dr. Kaye said. “If you can get this drug orally to someone with a functioning gut, it's the right thing to do, as opposed to using an IV.”

Oral linezolid is a clear alternative to intravenous vancomycin in patients who are doing well with the latter, he said. The major unique side effect of linezolid is thrombocytopenia, which occurs in at least 2% of patients, though usually only in those who take the drug longer than two weeks, he noted. Peripheral neuropathy can also occur in those on the drug for longer time periods, he said.

“Other concerns with linezolid are MAO-[monoamine oxidase] inhibition, and the potential to cause serotonin syndrome, especially in those patients who are on SSRIs [selective serotonin reuptake inhibitors],” Dr. Kaye said. “It's recommended to stop SSRIs or not give this drug to patients who are on them, but if a patient really needs linezolid, I will provide it even if he is on an SSRI. This is somewhat controversial.”

Oncology units or hospitals where the drug is heavily used often see an emergence of linezolid-resistant Enterococcus species, he warned. Other than that and its toxicities, the only other downside to the drug is price, he said. “If a patient's insurance doesn't cover it, you might get an alarming call saying, ‘Doc, I don't have $3,000 to pay for this.’ So make sure the insurance issues are taken care of.”

Another newish drug is daptomycin (brand name: Cubicin), which is FDA-indicated for SSTIs and bacteremia, including right-sided endocarditis. Practically, the intravenous drug has been shown to be noninferior to vancomycin for bloodstream infections, Dr. Kaye said.

“Linezolid has the pneumonia niche and daptomycin has the bloodstream infection niche,” he said.

The MIC (minimum inhibitory concentration) profile of daptomycin in some strains of MRSA is favorable to vancomycin, and it's increasingly common to switch to daptomycin when there is a vancomycin failure, “particularly if the MIC is borderline, like 2 [µg/mL],” Dr. Kaye said. “I think most hospitals are using vancomycin up front [with MRSA], but there is a lower threshold to switch off if there is a perceived nonresponse.”

While the dose for daptomycin in the package insert is 4 to 6 mg/kg of body weight once a day, Infectious Diseases Society of America guidelines recommend going as high as 8 to 10 mg/kg of body weight per day, he noted. Downsides to the drug are that it is expensive, the optimal dose is still unclear, it's only available intravenously, and it can increase creatine kinase in some patients. It also should not be used with pneumonia, as it is bound by surfactant and not active in the lungs, “so in your septic-looking patient with pneumonia, you might not be comfortable with daptomycin if you are worried that the source of the sepsis is the lung,” Dr. Kaye said.

Ceftaroline (brand name: Teflaro), which became available in February, is a fifth-generation cephalosporin, and the first cephalosporin to be active against MRSA. “This makes physicians like me and you guys feel good, to have an old, friendly beta-lactam that is now effective against MRSA,” Dr. Kaye said.

Ceftaroline is FDA-approved for community-acquired bacterial pneumonia and complicated SSTIs. Its practical uses are as a single-drug option for polymicrobial SSTIs and for pneumonia involving MRSA, Dr. Kaye said. Ceftaroline is competitively priced, but its clinical track record for MRSA is still limited, and its gram-negative coverage isn't as robust as other cephalosporins, he noted.

“It will be interesting to see where this drug finds its niche. Certainly, in some community-acquired pneumonia where MRSA is a concern, this would be one-stop shopping. Also, I think in some mild-to-moderate nursing home patients where MRSA is a concern and Pseudomonas isn't as much, ceftaroline might be good,” Dr. Kaye said.

Newer antimicrobials: The gram negatives

As far as gram-negative infections, doripenem (brand name: Doribax) might be a good option when carbapenem resistance to certain bacteria is a problem, Dr. Kaye said.

“If you are in an institution where carbapenem resistance among Pseudomonas is a problem, and it's not a high-level resistance, doripenem might offer an advantage in terms of increased activity. However, if Acinetobacter is a problem, it may not add all that much compared to the other carbapenems that are available,” he said.

A type 2 carbapenem that's indicated for complicated intra-abdominal infections and complicated urinary tract infections, doripenem is the only carbapenem that doesn't have a seizure risk mentioned in the package insert. While similar to imipenem and meropenem, the competitively priced doripenem has slightly better activity against Pseudomonas aeruginosa, Dr. Kaye said.

“It's an interesting drug but there's a question as to its role; people love their imipenem and meropenem, and this is the new kid on the block,” he said.

In hospitals with very high rates of carbapenem resistance among both Pseudomonas and Acinetobacter species, ertapenem (brand name: Invanz) might be a good choice, Dr. Kaye said. The sole type 1 carbapenem, ertapenem has very broad activity against gram positives and good gram-negative activity, including against extended-spectrum beta-lactamase (ESBL) enzymes.

“If you are treating an invasive infection due to ESBL, then this might be a good choice because you will decrease selective pressure on additional resistance for Pseudonomas and Acinetobacter. It's a narrower coverage that will still be active against ESBL but you won't get the collateral damage of selective antibiotic pressure when you don't need it,” he said.

Ertapenem is FDA-approved against intra-abdominal and pelvic infections, skin and skin-structure infections (including diabetic foot), community-acquired bacterial pneumonia and UTIs, and as prophylaxis for elective colorectal surgery. There are limited data on the effectiveness of this drug in the critically ill, Dr. Kaye cautioned. Its side effects are similar to the other carbapenems, but this drug is dosed only once a day, compared to two to four times a day with the others, he noted.

Another newish drug with broad-spectrum capability is tigecycline (brand name: Tygacil)—a “souped-up tetracycline” that is IV-only and has broad-spectrum capability. It's FDA-approved to treat complicated skin and skin-structure infections, complicated intra-abdominal infections and community-acquired pneumonia; it's also good consolidative therapy for polymicrobial SSTIs and intra-abdominal infections, Dr. Kaye said.

More information is needed about how this drug performs against multidrug-resistant gram-negative infections, he said. “When it comes to ESBLs, carbapenem-resistant Acinetobacter, etc., we are often going to be stuck with this drug as the only active agent against some of these MDR gram negatives,” Dr. Kaye said. “But we don't know a lot about how well this drug works in those patients.”

Limitations of the drug are its lower serum concentrations (“I would not count this as your only drug for a bloodstream infection or to cover a septic patient”) and published reports of resistance to gram negatives emerging during therapy, he said. Also, about 20% of patients experienced nausea and vomiting with the drug in research trials, although the incidence seems much lower in clinical practice, Dr. Kaye said.

Additionally, the FDA published a communication in September 2010 saying study patients on Tygacil saw an absolute increase in mortality of 4%, compared to 3% in patients on comparator antibiotics. Most of this effect came from pneumonia patients, Dr. Kaye noted.

“For severe pneumonia, even if it was Acinetobacter, I wouldn't use Tygacil as my only drug. I might use it in combination if no other options were available,” Dr. Kaye said. “For skin and soft-tissue infections and intra-abdominal infections in patients who aren't critically ill, I think it is a reasonable choice.”

Revisiting older drugs

Only a few antimicrobials have been approved by the FDA in the last few years, and only one of them addresses new issues related to gram-negative resistance, according to Dr. Kaye.

“Many pharmaceutical companies are getting out of the antibacterial business,” he said. “It simply isn't profitable to sink money into a drug that may or may not make it to market, and which patients may get for a week or two, compared to years and years with something like an antidepressant or antihypertensive.”

As such, researchers and physicians are turning to older antimicrobials to fill in the gaps, despite some of their toxicity profiles—which often were based on higher doses than are used now, he said. “The dry industry pipeline has really led to increased utilization of some older drugs—and in some instances older toxic drugs—for new indications and new types of resistant pathogens,” said Dr. Kaye.

Examples of older drugs that are being used in new ways include:

  • Trimethoprim-sulfamethoxazole (brand name: Bactrim) for MRSA. “I think its big role is in treating skin and soft-tissue infections due to community-acquired MRSA, which often involve a carbuncle or boil. Incision and drainage is the most important component, but the patient also needs antibiotic therapy. Trimethoprim-sulfamethoxazole is also active in the lung and you get good serum concentrations, so that's a pretty nice triple play right there,” Dr. Kaye said. The drawback to this drug is toxicity; it can cause hypersensitivity or cutaneous reactions. It can also cause hyperkalemia, especially in older adults or those with renal insufficiency, so “you need to gauge how well you can monitor the potassium for the patient and what their renal function is like,” he said. Bone marrow suppression is a risk, as well, he said, so marrow should also be monitored for patients who are on the drug longer than a week.
  • Colistin for MDR organisms. Clinical experience with colistin is observational. Patients who try it have often been on other drugs first, so there is a big delay in effective therapy, and the patients are very sick. “We've been forced to use colistin to treat certain strands of Acinetobacter, Pseudomonas and carbapenem-resistant Enterobacteriaceae. It's an important drug we are trying to understand more about—the National Institutes of Health are sponsoring several studies on colistin in clinical settings—but I wouldn't use it unless you have a high suspicion for an MDR organism for which there aren't other good options,” Dr. Kaye said. Nephrotoxicity is this drug's big downside; about 40% of patients at Detroit Medical Center develop renal insufficiency with colistin, he said.
  • Fosfomycin (brand name: Monurol) for MRSA, VRE and ESBL. This drug is bactericidal and has “excellent” activity against MRSA, VRE and ESBL, Dr. Kaye said. It has been available in IV form in Europe for some time, but is only available in oral form in the U.S., and is only FDA-approved for urinary tract infection. It gets into the urine well, but not the bloodstream, he noted: “If you've any concern about an upper tract infection, this would not be a good choice because the bioavailability is low.”
  • Aminoglycosides as part of combination therapy for MDR Pseudomonas species infections. There isn't a lot of experience using these drugs as monotherapy for basic infections; they are usually part of a combination, Dr. Kaye said. Aminoglycosides carry a risk of nephrotoxicity and ototoxicity. “With gram-negative sepsis, if you had a choice of active beta-lactam or aminoglycoside, most would choose the beta-lactam. So aminoglycosides are there, but as single drugs, they are not going to be a cure-all,” he said.
  • Rifampin (brand names: Rifadin, Rimactane) as part of combination therapy against MRSA. The drug has retained activity against many strains of MRSA and has synergistic activity for treating MDR gram negatives, Dr. Kaye said. “The problem with rifampin is you can't use it as single-drug therapy, because resistance rapidly emerges. In combination, though, particularly in complicated cases like meningitis, rifampin penetrates the central nervous system fairly well,” he said.

Dr. Kaye's disclosures included research grants/contracts with Merck & Co., Inc.; honoraria and speakers bureau appointments from Merck, Pfizer Inc. and Cubist Pharmaceuticals, Inc; and consultantships with Merck, Pfizer and Forrest Pharmaceuticals, Inc.